Non-invasive Neurostimulation Research Articles

Theta burst stimulation ameliorates symptoms of experimental autoimmune encephalomyelitis and attenuates reactive gliosis

Multiple sclerosis (MS) is a chronic neurodegenerative disease caused by inflammatory processes in the central nervous system (CNS). Decades of research led to discovery of several disease-modifying therapeutics strategies with moderate success. Experimental autoimmune encephalomyelitis (EAE) is currently the most commonly used experimental model for MS and for studying various therapeutic approaches. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neurostimulation technique with multiple beneficial effects on healthy as well as CNS with pathology. However, the molecular and cellular mechanisms of rTMS on acute EAE are scarce. Our study demonstrated beneficial effects of theta-burst stimulation (TBS), an experimental paradigm of rTMS, on disease course of acute EAE. TBS treatment attenuated reactive gliosis, restored myelin sheet and down-regulated expression of vimentin in EAE rats. These effects were reflected through reduced clinical parameters, shorter duration of illness and days spent in paralysis. Based on our research, rTMS deserves further considerations for its neuroprotective effect on EAE, and is an excellent candidate for further research and points that it could be used for more than for simple symptomatic therapy.

External trigeminal nerve stimulation for drug resistant epilepsy: A randomized controlled trial

BackgroundExternal trigeminal nerve stimulation (ETNS) is an emergent, non-invasive neurostimulation therapy delivered bilaterally with adhesive skin electrodes. In previous studies, ETNS was associated to a decrease in seizure frequency in patients with focal drug-resistant epilepsy (DRE). ObjectiveTo determine the long-term efficacy and tolerability of ETNS in patients with focal DRE. Moreover, to explore whether its efficacy depends on the epileptogenic zone (frontal or temporal), and its impact on mood, cognitive function, quality of life, and trigeminal nerve excitability. MethodsForty consecutive patients with frontal or temporal DRE, unsuitable for surgery, were randomized to ETNS or usual medical treatment. Participants were evaluated at 3, 6 and 12 months for efficacy, side effects, mood scales, neuropsychological tests and trigeminal nerve excitability. ResultsSubjects had a median of 15 seizures per month and had tried a median of 12.5 antiepileptic drugs. At 12 months, percentage of responders was 50% in ETNS group and 0% in control group. Seizure frequency in ETNS group decreased by −43.5% from baseline. Temporal epilepsy subgroup responded better than frontal epilepsy subgroup (55.56% vs. 45.45%, respectively). Median stimulation intensity was 6.2 mA. ETNS improved quality of life, but not anxiety or depression. Long-term ETNS affected neither neuropsychological function, nor trigeminal nerve excitability. No relevant adverse events were observed. ConclusionsETNS is an effective and well-tolerated therapy for focal DRE. Patients with temporal epilepsy showed a better response than those with frontal epilepsy. Future studies with larger populations may define its role compared to other neurostimulation techniques. Classification of evidenceThis study provides Class II evidence that ETNS reduces seizure frequency in patients with focal DRE.

Modulation of auditory gamma-band responses using transcranial electrical stimulation.

Auditory gamma-band (>30 Hz) activity is a biomarker of cortical excitation/inhibition (E/I) balance in autism, schizophrenia, and bipolar disorder. We provide a comprehensive account of the effects of transcranial alternating current stimulation (tACS) and transcranial direct current stimulation (tDCS) on gamma responses. Forty-five healthy young adults listened to 40-Hz auditory click trains while electroencephalography (EEG) data were collected to measure stimulus-related gamma activity immediately before and after 10 min of 1 mA tACS (40 Hz), tDCS, or sham stimulation to left auditory cortex. tACS, but not tDCS, increased gamma power and phase locking to the auditory stimulus. However, both tACS and tDCS strengthened the gamma phase connectome, and effects persisted beyond the stimulus. Finally, tDCS strengthened the coupling of gamma activity to alpha oscillations after termination of the stimulus. No effects were observed in prestimulus gamma power, the gamma amplitude connectome, or any band-limited alpha measure. Whereas both stimulation techniques synchronize gamma responses between regions, tACS also tunes the magnitude and timing of gamma responses to the stimulus. Results reveal dissociable neurophysiological changes following tACS and tDCS and demonstrate that clinical biomarkers can be altered with noninvasive neurostimulation, especially frequency-tuned tACS.NEW & NOTEWORTHY Gamma frequency-tuned transcranial alternating current stimulation (tACS) adjusts the magnitude and timing of auditory gamma responses, as compared with both sham stimulation and transcranial direct current stimulation (tDCS). However, both tACS and tDCS strengthen the gamma phase connectome, which is disrupted in numerous neurological and psychiatric disorders. These findings reveal dissociable neurophysiological changes following two noninvasive neurostimulation techniques commonly applied in clinical and research settings.

An Efficient Noninvasive Neuromodulation Modality for Overactive Bladder Using Time Interfering Current Method.

The present study aimed to evaluate a new tibial nerve stimulation (TNS) modality, which uses interferential currents, in terms of the stimulation electric field penetration efficiency into the body and physiological effectiveness. In silico experiments were performed to analyze the penetration efficiency of proposed interferential current therapy (ICT). Based on this, we performed in vivo experiments to measure excitation threshold of ICT for the tibial nerve, which is related to stimulation field near the nerve. Regarding analysis of the physiological effectiveness, in vivo ICT-TNS was performed, and changes in bladder contraction frequency and voiding volume were measured. The penetration efficiency and physiological effectiveness of ICT were evaluated by comparison with those of conventional TNS using transcutaneous electrical nerve stimulation (TENS). Simulation results showed that ICT has high penetration efficiency, thereby generating stronger field than TENS. These results are consistent with the in vivo results that nerve excitation threshold of ICT is lower than that of TENS. Moreover, ICT-TNS decreased contraction frequency and increased voiding volume, and its performance was profound compared with that of TENS-TNS. The proposed ICT is more efficient in inducing the stimulation field near the tibial nerve placed deep inside the body compared with conventional TENS and shows a good clinical effectiveness for TNS. The high efficiency of ICT increases the safety of noninvasive neurostimulation; therefore, it has clinical potential to become a promising modality for TNS to treat OAB and other peripheral neurostimulations.

Moving beyond belief: A narrative review of potential biomarkers for transcutaneous vagus nerve stimulation.

Transcutaneous vagus nerve stimulation (tVNS) is a non-invasive neurostimulation technique that is currently being tested as a potential treatment for a myriad of neurological and psychiatric disorders. However, the working mechanisms underlying tVNS are poorly understood and it remains unclear whether stimulation activates the vagus nerve for every participant. Finding a biological marker of tVNS is imperative, as it can help guide research on clinical applications and can inform researchers on optimal stimulation sites and parameters to further optimize treatment efficacy. In this narrative review, we discuss five potential biomarkers for tVNS and review currently available evidence for these markers for both invasive and tVNS. While some of these biomarkers hold promise from a theoretical perspective, none of the potential biomarkers provide clear and definitive indications that tVNS increases the vagal activity or augments activity in the locus coeruleus-noradrenaline network. We conclude the review by providing several recommendations for how to tackle the challenges and opportunities when researching potential biomarkers for the effects of tVNS.

P197 Modulation of cortical activity with non-invasive neurostimulation in children and adolescents with autism spectrum disorder – a randomized, double-blind and sham-controlled study

P197 Modulation of cortical activity with non-invasive neurostimulation in children and adolescents with autism spectrum disorder – a randomized, double-blind and sham-controlled study

Antibody-Conjugated Barium Titanate Nanoparticles for Cell-Specific Targeting.

Barium titanate nanoparticles (BTNPs) are gaining popularity in biomedical research because of their piezoelectricity, nonlinear optical properties, and high biocompatibility. However, the potential of BTNPs is limited by the ability to create stable nanoparticle dispersions in water and physiological media. In this work, we report a method of surface modification of BTNPs based on surface hydroxylation followed by covalent attachment of hydrophilic poly(ethylene glycol) (PEG) polymers. This polymer coating allows for additional modifications such as fluorescent labeling, surface charge tuning, or directional conjugation of IgG antibodies. We demonstrate the conjugation of anti-EGFR antibodies to the BTNP surface and show efficient molecular targeting of the nanoparticles to A431 cells. Overall, the reported modifications aim to expand the BTNP applications in molecular imaging, cancer therapy, or noninvasive neurostimulation.

Noninvasive Brain Stimulation in Epilepsy.

Neurostimulation in epilepsy is a long standing established concept, and through experimental and clinical uses, our understanding of neurostimulation and neuromodulation has grown substantially. Noninvasive brain stimulation techniques use electromagnetic principles to noninvasively modulate brain activity in a spatiotemporally targeted manner. This review focused on the two predominant forms of noninvasive neurostimulation: transcranial magnetic stimulation (TMS) and transcranial direct current stimulation, and their current applications in the diagnosis and management of epilepsy. A number of small randomized sham-controlled studies suggest that both TMS and transcranial direct current stimulation may have a beneficial effect in decreasing seizure frequency in patients with medically refractory epilepsy, without significant side effects. Small pilot studies also suggest that TMS in combination with EEG may be used to develop quantitative biomarkers of cortical hyperexcitability in patients with epilepsy. Furthermore, TMS is already Food and Drug Administration-cleared for presurgical mapping of eloquent cortex, and preliminary studies suggest that navigated TMS represents a highly valuable clinical supplement for preoperative functional planning. Transcranial magnetic stimulation and transcranial direct current stimulation have shown great potential benefit for patients with epilepsy; however, further large multicenter randomized sham-controlled studies are needed to better optimize stimulation settings and protocols, define mechanisms of action, assess long-term effects, and clearly define roles and determine efficacy.

Non-invasive neurostimulation in migraine

Migraine is the most common chronic neurological disease. Migraine is in the top 5 causes that reduce the quality of life. In recent years, neuromodulation techniques are successfully used with primary headaches. Several variants of non-invasive neuromodulation have been shown to be effective in various forms of migraine. This review analyzes clinical trials and case reports of the effectiveness and safety of non-invasive stimulation of the first branch of the trigeminal nerve in migraine.

Update on noninvasive neuromodulation for migraine treatment-Vagus nerve stimulation.

Noninvasive neurostimulation methods are particularly suited for migraine treatment thanks to their most favorable adverse event profile. Among them, noninvasive vagus nerve stimulation (nVNS) has raised great hope because of the role the vagus nerve is known to play in pain modulation, inflammation and brain excitability. We will critically review the clinical studies performed for migraine attack treatment and migraine prevention with the GammaCore® device, which allows cervical vagus nerve stimulation. nVNS is effective for the abortive treatment of migraine attacks, although the effect size is modest and numbers-to-treat appear not superior to those of other noninvasive neurostimulation methods, and inferior to those of oral triptans. The effect of nVNS with the GammaCore® in migraine prevention is not superior to sham stimulation, except possibly in patients with high adherence to the treatment. Both in acute and preventive trials, nVNS was characterized by an outstanding tolerance and safety profile, like the other noninvasive neurostimulation techniques. In physiological animal and human studies, cervical nVNS was shown to generate somatosensory evoked responses, to modulate pain perception and several areas of the cerebral pain network, and to inhibit experimental cortical spreading depression, which are relevant effects for migraine therapy.

Oropharyngeal dysphagia in stroke: diagnostic and therapeutic aspects

The prevalence of oropharyngeal dysphagia is high after a stroke. Clinically, it manifests as alterations affecting swallowing efficiency and safety, with the consequent morbidity and mortality associated with nutritional and respiratory alterations. To carry out an updated review of the diagnostic and therapeutic aspects of oropharyngeal dysphagia after a stroke that can be applied in daily clinical practice, and of the non-invasive neurostimulation techniques. The process of diagnosis and treatment of oropharyngeal dysphagia aims to screen, identify and diagnose patients at risk of dysphagia, and establish the dietary and therapeutic measures that ensure proper nutrition and hydration of patients under safe conditions. The diagnosis is based on the clinical examination of swallowing and on instrumental examinations such as videofluoroscopy and fibro-endoscopy. Therapeutic measures include compensatory and rehabilitative strategies (active manoeuvres, motor control exercises, neuromuscular electrostimulation and botulinum toxin treatment). Neurostimulation techniques include non-invasive central stimulation and intrapharyngeal electrical stimulation. The prevalence of oropharyngeal dysphagia is high after a stroke. Diagnosis should include a clinical evaluation and an instrumental examination, and thus objectively indicate the treatment, which will include compensatory and restorative measures with which to reduce the associated morbidity and mortality.

Safety and tolerability of transcranial magnetic and direct current stimulation in children: Prospective single center evidence from 3.5 million stimulations

BackgroundNon-invasive brain stimulation is being increasingly used to interrogate neurophysiology and modulate brain function. Despite the high scientific and therapeutic potential of non-invasive brain stimulation, experience in the developing brain has been limited. ObjectiveTo determine the safety and tolerability of non-invasive neurostimulation in children across diverse modalities of stimulation and pediatric populations. MethodsA non-invasive brain stimulation program was established in 2008 at our pediatric, academic institution. Multi-disciplinary neurophysiological studies included single- and paired-pulse Transcranial Magnetic Stimulation (TMS) methods. Motor mapping employed robotic TMS. Interventional trials included repetitive TMS (rTMS) and transcranial direct current stimulation (tDCS). Standardized safety and tolerability measures were completed prospectively by all participants. ResultsOver 10 years, 384 children underwent brain stimulation (median 13 years, range 0.8–18.0). Populations included typical development (n = 118), perinatal stroke/cerebral palsy (n = 101), mild traumatic brain injury (n = 121) neuropsychiatric disorders (n = 37), and other (n = 7). No serious adverse events occurred. Drop-outs were rare (<1%). No seizures were reported despite >100 participants having brain injuries and/or epilepsy. Tolerability between single and paired-pulse TMS (542340 stimulations) and rTMS (3.0 million stimulations) was comparable and favourable. TMS-related headache was more common in perinatal stroke (40%) than healthy participants (13%) but was mild and self-limiting. Tolerability improved over time with side-effect frequency decreasing by >50%. Robotic TMS motor mapping was well-tolerated though neck pain was more common than with manual TMS (33% vs 3%). Across 612 tDCS sessions including 92 children, tolerability was favourable with mild itching/tingling reported in 37%. ConclusionsStandard non-invasive brain stimulation paradigms are safe and well-tolerated in children and should be considered minimal risk. Advancement of applications in the developing brain are warranted. A new and improved pediatric NIBS safety and tolerability form is included.

Transcranial Electrical Stimulation and Recording of Brain Activity using Freestanding Plant‐Based Conducting Polymer Hydrogel Composites

AbstractTranscranial electrical stimulation is a noninvasive neurostimulation technique with a wide range of therapeutic applications. However, current electrode materials are typically not optimized for this abiotic/biotic interface which requires high charge capacity, operational stability, and conformability. Here, a plant‐based composite electrode material based on the combination of aloe vera (AV) hydrogel and a conducting polymer (CP; poly(3,4‐ethylenedioxythiophene):polystyrene sulfonate, PEDOT:PSS) is reported. This material system is fabricated into films and provides biocompatibility, conformability, and stability, while offering desirable electrical properties of the PEDOT:PSS. AVCP films are also molded onto the rough surface of the skull leading to a mechanically stable and robust interface. The in vivo efficacy of the AVCP films is verified to function as stimulating and recording electrodes by placing them on the skull of a rat and concomitantly inducing focal seizures and acquiring the evoked neural activity. AVCP films pave the way for high‐quality biological interfaces that are broadly applicable and can facilitate advances in closed‐loop responsive stimulation devices.

Sex differences in fatigability and recovery relative to the intensity-duration relationship.

Females demonstrate greater fatigue resistance than males during contractions at intensities relative to maximum force. However, previous studies have not accounted for the influence of metabolic thresholds on fatigability. This study is the first to test whether sex differences in fatigability exist when exercise intensity is normalised relative to a metabolic threshold: the critical intensity derived from assessment of the intensity-duration relationship during intermittent, isometric knee extensor contractions. We show that critical intensity in females occurred at a higher percentage of maximum force compared to males. Furthermore, females demonstrated greater fatigue resistance at exercise intensities above and below this metabolic threshold. Our data suggest that the sex difference was mediated by lesser deoxygenation of the knee extensors during exercise. These data highlight the importance of accounting for metabolic thresholds when comparing fatigability between sexes, whilst emphasising the notion that male data are not generalisable to female populations. Females are less fatigable than males during isometric exercise at intensities relative to maximal voluntary contraction (MVC); however, whether a sex difference in fatigability exists when exercise is prescribed relative to a critical intensity is unknown. This study established the intensity-duration relationship, and compared fatigability and recovery between sexes following intermittent isometric contractions normalised to critical intensity. Twenty participants (10females) completed four intermittent isometric knee extension trials to task failure to determine critical intensity and the curvature constant (W'), followed by fatiguing tasks at +10% and -10% relative to critical intensity. Neuromuscular assessments were completed at baseline and for 45min post-exercise. Non-invasive neurostimulation, near-infrared spectroscopy, and non-invasive haemodynamic monitoring were used to elucidate the physiological mechanisms responsible for sex differences. Females demonstrated a greater critical intensity relative to MVC than males (25 ± 3 vs. 21 ± 2% MVC, P=0.003), with no sex difference for W' (18,206 ± 6331 vs. 18,756 ± 5762Ns, P=0.850). Time to task failure was greater for females (62.37 ± 17.25 vs. 30.43 ± 12.75min, P<0.001) during the +10% trial, and contractile function recovered faster post-exercise (P=0.034). During the -10% trial females experienced less contractile dysfunction (P=0.011). Throughout the +10% trial, females demonstrated lesser decreases in deoxyhaemoglobin (P=0.007) and an attenuated exercise pressor reflex. These data show that a sex difference in fatigability exists even when exercise is matched for critical intensity. We propose that greater oxygen availability during exercise permits females to sustain a higher relative intensity than males, and is an explanatory factor for the sex difference in fatigability during intermittent, isometric contractions.

Arbitration Between Habitual and Goal-directed Behavior in Obsessive-compulsive Disorder: Circuit Dynamics and Effects of Noninvasive Neurostimulation

Arbitration Between Habitual and Goal-directed Behavior in Obsessive-compulsive Disorder: Circuit Dynamics and Effects of Noninvasive Neurostimulation

Noninvasive neurostimulation of left temporal lobe disrupts rapid talker adaptation in speech processing

Talker adaptation improves speech processing efficiency by reducing possible mappings between talkers’ speech acoustics and listeners’ phonemic representations. We investigated the functional neuroanatomy of talker adaptation by applying noninvasive neurostimulation (high-definition transcranial direct current stimulation; HD-tDCS) to left superior temporal lobe while participants performed an auditory word identification task. We factorially manipulated talker variability (single vs. mixed talkers) and speech context (isolated words vs. connected speech), measuring listeners’ speech processing efficiency under anodal, cathodal, or sham stimulation. Speech processing was faster for single talkers than mixed talkers, and connected speech reduced the additional processing costs associated with mixed-talker speech. However, the beneficial effect of connected speech in the mixed-talker condition was significantly attenuated under both anodal and cathodal stimulation versus sham. Stimulation of left superior temporal lobe disrupts the brain’s ability to use local phonetic context to rapidly adapt to a talker, revealing this region’s causal role in talker adaptation.

Replacing tDCS with theta tACS provides selective, but not general WM benefits

Working memory (WM) can be improved after repeated training sessions paired with noninvasive neurostimulation techniques. Previously, we reported that WM training paired with tDCS succeeded behaviorally by enhancing anterior-posterior theta phase coherence and reducing alpha power. Here, in two experiments we tested several theta and alpha frequencies and two transcranial alternating current stimulation (tACS) montages in an effort to shortcut WM training while preserving behavioral gains. In Experiment 1, in separate sessions participants received online tACS at two frequencies derived from the previous study with the respective goal of improving and impairing WM performance. We selected the mean group peak value theta (7 Hz) to benefit WM and alpha (11 Hz) to impair WM. Stimulation (tACS) over right frontoparietal sites (F4-P4) during 3-back WM tasks (object, spatial) produced no behavioral consequences. In Experiment 2 we stimulated at a slower theta frequency (4.5 Hz), which was also significant in our prior study, and tested whether frontoparietal or bifrontal montages would be more effective at improving WM. This experiment revealed selectively improved object WM after right frontoparietal tACS alone. In summary, one session of tACS failed to produce the magnitude or breadth of WM gains observed after 4–10 tDCS-WM training sessions. In short, despite looking for loopholes we found little tACS savings.

A Prospective Open-Label Pilot Study of Transcranial Direct Current Stimulation in High-Functioning Autistic Patients with a Dysexecutive Syndrome

Background: Executive functions (EF) are often impaired in autism spectrum disorder (ASD). Such dysfunctions are associated with anxiety, depression, and a lack of autonomy. Transcranial direct current stimulation (tDCS) has been shown to enhance EF in healthy adults and clinical populations and to improve working memory − a component of the EF − in adults with high-functioning ASD (HF-ASD). We hypothesized that tDCS could improve the EF of HF-ASD patients. Such enhancement could improve their adaptive behaviors. Method: Eight patients with HF-ASD received 10 consecutive cathodal tDCS sessions (2 mA) over the left dorsolateral prefrontal cortex (F3) for 15 min each in an open trial. EF (with the Stroop test, Trail Making Test [TMT] A and B, Modified Wisconsin Card Sorting Test [mWCST], and Verbal Fluency Test) and behavioral dysexecutive syndrome (with the Behavioral Dysexecutive Syndrome Inventory and the Repetitive and Restricted Behaviour scale) were assessed before and 10 days after treatment. Results: This study showed significant improvement in initiation (TMT-A time: p = 0.018) and cognitive flexibility (TMT-B time: p = 0.009; letter Verbal Fluency Test: p = 0.017; mWCST total errors: p = 0.028) after tDCS. Regarding behavior, the hypoactivity of the patients improved, as well as their repetitive and restrictive behaviors. In addition, this noninvasive neurostimulation technique was well tolerated. Conclusions: Flexibility and initiation are the most impaired EF in autism. These are promising results which justify a randomized and placebo-controlled study in a wider population. If these results were confirmed by a randomized controlled trial, tDCS could be an easy and well-tolerated adjunctive treatment aiming to improve the quality of life and the autonomy of ASD patients.

A multiple modulation synthesis method with high spatial resolution for noninvasive neurostimulation.

Noninvasive neurostimulation plays a pivotal role in the direct control of neural circuits and the modulation of neuronal function. However, it is difficult to balance both spatial resolution and penetration depth when stimulating deep neurons. Here, we designed a multiple (time-division, frequency and polarity) modulation synthesis (MMS) method for noninvasively stimulating deep neurons with low-frequency envelopes. Compared to conventional transcranial electrical stimulation, we demonstrated that it can stimulate deep neurons at the desired firing rate (beat frequency) with higher spatial resolution via a computational model combining finite element analysis and Hodgkin-Huxley action potential model. Additionally, we measured the distribution of stimulus waveforms in saline solution to validate its effect. Taken together, the results of this study indicate that MMS stimulation with higher spatial resolution is steerable and might be a potential alternative to traditional implanted electrodes.

Transcranial Focused Ultrasound (tFUS) and Transcranial Unfocused Ultrasound (tUS) Neuromodulation: From Theoretical Principles to Stimulation Practices.

Transcranial focused ultrasound is an emerging technique for non-invasive neurostimulation. Compared to magnetic or electric non-invasive brain stimulation, this technique has a higher spatial resolution and can reach deep structures. In addition, both animal and human studies suggest that, potentially, different sites of the central and peripheral nervous system can be targeted by this technique. Depending on stimulation parameters, transcranial focused ultrasound is able to determine a wide spectrum of effects, ranging from suppression or facilitation of neural activity to tissue ablation. The aim is to review the state of the art of the human transcranial focused ultrasound neuromodulation literature, including the theoretical principles which underlie the explanation of the bioeffects on neural tissues, and showing the stimulation techniques and parameters used and their outcomes in terms of clinical, neurophysiological or neuroimaging results and safety.